FXTAS: Neuropsychological/neuropsychiatric phenotypes

Abstract

Data concerning the neuropsychological and neuropsychiatric phenotypes of the fragile X-associated tremor/ataxia syndrome (FXTAS) are providing an increasingly clear picture of the cognitive and behavioral features of this neurodegenerative disorder. This is true especially for males, among whom FXTAS has been reasonably well characterized. As FXTAS is a recently identified disorder, despite a considerable amount of research, many questions remain. For example, women, in part because of the presence of a normal allele on the second X chromosome, tend to have significant differences in penetrance and expression of FMR1 gene mutations; hence there are marked gender differences in the phenotype, and relatively little is known about the female phenotype. Moreover, the factors that account for severity and progression within a given individual are as yet unclear. This chapter addresses studies of the cognitive and emotional signs and symptoms of FXTAS, especially insofar as they are seen in males. We summarize what is known about cognition and psychiatric functioning in affected individuals and consider some of the many unknowns. For the most part, the neuropsychological deficits associated with FXTAS involve impaired executive cognitive functioning. Hence, one frequently observes disorders of behavioral self-regulation, planning, inhibition, working memory, and information processing. These deficits appear to interact with, and contribute to, psychiatric symptomatology such as anxiety, impulsivity, apathy, irritability, and agitation. Most studies to date have been cross-sectional, and it is not yet possible to draw inferences regarding the progression and timing of cognitive decline in FXTAS. Moreover, as some individuals with FXTAS have minimal or no cognitive/psychiatric impairment, even in the presence of significant neurological deficits, these manifestations of the disorder may be quite heterogeneous. Further research will enhance our understanding of this disorder, of the temporal and symptomatic relationships between neuropsychological and neurological findings, and of other genetic and epigenetic variables that determine the development, course, penetrance, and severity of FXTAS.